Antibodies Binding to Alpha-Synuclein for Therapy and Diagnosis

Abstract

The present invention relates to novel molecules that can be employed for the prevention, alleviation, treatment and/or diagnosis of diseases, disorders and abnormalities associated with alpha-synuclein (α-synuclein, A-synuclein, aSynuclein, A-syn, α-syn, aSyn, a-syn) aggregates, including, but not limited to, Lewy bodies and/or Lewy neurites, such as Parkinson's disease, Multiple System Atrophy, Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (PDD)) or Diffuse Lewy Body Disease. The invention relates to alpha-synuclein binding molecules, in particular to alpha-synuclein antibodies or an antigen-binding fragment or a derivative thereof and uses thereof. The present molecules can also be used for determining a predisposition to such a disorder, disease or abnormality, monitoring residual disorder, disease or abnormality, or predicting the responsiveness of a patient who is suffering from such a disorder, disease or abnormality to treatment with a certain medicament.

1 .- 71 . (canceled) 
     
     
         72 . An alpha-synuclein binding molecule, which comprises:
 a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 691; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 692; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 693; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 695; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 696; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 697; or   b) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 721; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 722; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 723; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 725; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   c) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 671; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 742; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 743; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 675; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 676; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 677; or   d) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 791; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 792; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 793; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 795; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 797; or   e) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 841; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 842; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 843; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 845; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 846; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 847; or   f) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 611; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 612; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 613; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 615; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 617; or   g) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 621; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 622; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 623; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 625; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 626; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 627; or   h) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 631; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 632; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 633; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 635; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   i) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 641; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 642; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 643; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 625; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 626; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 627; or   j) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 621; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 642; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 653; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 655; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 626; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 627; or   k) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 661; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 662; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 663; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 665; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 666; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 667; or   l) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 671; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 672; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 673; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 675; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 676; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 677; or   m) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 621; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 642; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 683; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 625; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 686; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 627; or   n) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 701; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 702; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 703; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 705; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 706; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 707; or   o) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 711; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 712; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 713; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 715; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 716; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 717; or   p) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 731; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 722; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 733; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 735; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 736; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   q) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 751; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 722; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 723; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 735; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   r) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 761; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 722; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 733; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 765; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   s) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 771; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 772; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 773; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 675; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 676; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 677; or   t) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 771; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 802; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 803; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 805; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 676; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 677; or   u) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 811; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 812; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 813; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 815; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 696; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 817; or   v) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 821; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 822; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 823; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 825; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 826; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 827; or   w) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 831; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 832; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 833; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 835; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 836; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 817.   
     
     
         73 . The alpha-synuclein binding molecule of  claim 72 , which:
 (i) inhibits or delays seeded or spontaneous alpha-synuclein aggregation; and   (ii) is capable of recognizing and binding to pathological or aggregated alpha-synuclein, particularly human alpha-synuclein, in vitro or in vivo.   
     
     
         74 . The alpha-synuclein binding molecule of  claim 72 , which is an antibody or an antibody-binding fragment thereof comprising:
 a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 691; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 692; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 693; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 695; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 696; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 697; or   b) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 721; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 722; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 723; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 725; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 637; or   c) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 671; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 742; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 743; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 675; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 676; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 677; or   d) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 791; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 792; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 793; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 795; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 616; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 797; or   e) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 841; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 842; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 843; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 845; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 846; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 847.   
     
     
         75 . The alpha-synuclein binding molecule of  claim 72 , which is an antibody or an antibody-binding fragment thereof comprising:
 a. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 690 or a heavy chain variable region (VH) having at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 690; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 694 or a light chain variable region (VL) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 694; or   b. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 720; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 724 or a light chain variable region (VL) having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 724; or   c. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 740 or a heavy chain variable region (VH) having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 740; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 744 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 744; or   d. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 790 or a heavy chain variable region (VH) having at least 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 790; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 794 or a light chain variable region (VL) having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 794; or   e. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 840 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 840; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 844; or   f. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 610 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 610; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 614; or   g. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 620 or a heavy chain variable region (VH) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 620; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 624 or a light chain variable region (VL) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 624; or   h. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 630 or a heavy chain variable region (VH) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 630; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 634 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 634; or   i. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 640 or a heavy chain variable region (VH) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 640; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 644 or a light chain variable region (VL) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 644; or   j. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 650 or a heavy chain variable region (VH) having at least 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 650; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 654 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 654; or   k. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 660 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 660; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 664 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 664; or   l. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 670 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 670; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 674; or   m. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 680 or a heavy chain variable region (VH) having at least 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 680; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 684 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 684; or   n. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 700 or a heavy chain variable region (VH) having at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 700; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 704 or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 704; or   o. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 710 or a heavy chain variable region (VH) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 710; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 714 or a light chain variable region (VL) having at least 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 714; or   p. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 730 or a heavy chain variable region (VH) having at least 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 730; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 734 or a light chain variable region (VL) having at least 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 734; or   q. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 750 or a heavy chain variable region (VH) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 750; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 754 or a light chain variable region (VL) having at least 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 754; or   r. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 760 or a heavy chain variable region (VH) having at least 97%, 98%, 99% sequence identity to the amino acid sequence of SEQ ID NO: 760; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 764 or a light chain variable region (VL) having at least 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 764; or   s. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 770 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 770; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 774 or a light chain variable region (VL) having at least 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 774; or   t. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 750 or a heavy chain variable region (VH) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 750; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 784 or a light chain variable region (VL) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 784; or   u. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 800 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 800; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 804 or a light chain variable region (VL) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 804; or   v. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 810 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 810; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 814 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 814; or   w. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 820 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 820; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 824 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 824; or   x. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 830 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 830; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 834.   
     
     
         76 . The alpha-synuclein binding molecule of  claim 72 , which is an antibody or an antibody-binding fragment thereof comprising:
 a. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 690 or a heavy chain variable region (VH) having at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 690; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 694 or a light chain variable region (VL) having at least 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 694; or   b. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 720; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 724 or a light chain variable region (VL) having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 724; or   c. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 740 or a heavy chain variable region (VH) having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 740; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 744 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 744; or   d. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 790 or a heavy chain variable region (VH) having at least 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 790; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 794 or a light chain variable region (VL) having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 794; or   e. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 840 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 840; and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 844.   
     
     
         77 . The alpha-synuclein binding molecule of  claim 72 , which is an antibody or an antibody-binding fragment thereof comprising:
 a. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 690 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 694; or   b. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 720 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 724; or   c. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 740 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 744; or   d. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 790 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 794; or   e. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 840 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 844; or   f. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 610 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 614; or   g. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 620 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 624; or   h. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 630 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 634; or   i. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 640 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 644; or   j. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 650 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 654; or   k. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 660 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 664; or   l. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 670 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 674; or   m. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 680 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 684; or   n. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 700 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 704; or   o. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 710 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 714; or   p. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 730 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 734; or   q. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 750 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 754; or   r. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 760 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 764; or   s. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 770 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 774; or   t. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 750 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 784; or   u. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 800 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 804; or   v. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 810 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 814; or   w. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 820 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 824; or   x. a Heavy Chain Variable Region (VH) comprising the sequence of SEQ ID NO: 830 and a Light Chain Variable Region (VL) comprising the sequence of SEQ ID NO: 834.   
     
     
         78 . The alpha-synuclein binding molecule of  claim 72 , which binds to an epitope within amino acids residues 1-15 (SEQ ID NO: 121), 15-45 (SEQ ID NO: 138), 19-33 (SEQ ID NO: 123), 28-50 (SEQ ID NO: 139), 31-60 (SEQ ID NO: 146), 81-120 (SEQ ID NO: 137), 91-105 (SEQ ID NO: 131), 96-140 (SEQ ID NO: 147) or 100-114 (SEQ ID NO: 132) of human alpha-synuclein of SEQ ID NO: 1, or
 to a non-linear epitope within human alpha-synuclein of SEQ ID NO: 1.   
     
     
         79 . The alpha-synuclein binding molecule of  claim 72 , which:
 a. delays the aggregation and seeding of pathological alpha-synuclein in vivo and/or in vitro;   b. delays or inhibits the propagation of alpha-synuclein aggregates; or   c. upon pre-incubation with alpha-synuclein seeds causes an at least 10 percent increase in aggregation half-time (τ½ values) of seeded aggregation relative to the seeded aggregation in the absence of binding molecule, optionally wherein alpha-synuclein aggregation is monitored by a thioflavin T (ThT) fluorescence assay.   
     
     
         80 . The alpha-synuclein binding molecule of  claim 72 , which:
 a. binds (in a Parkinson's disease (PD) context) to pathological and/or aggregated alpha-synuclein in Lewy bodies and Lewy neurites; or   b. binds (in a multiple system atrophy (MSA) context) to pathological and/or aggregated alpha-synuclein in glial cytoplasmic inclusions.   
     
     
         81 . The alpha-synuclein binding molecule of  claim 72 , which is:
 a. an antibody or an antigen-binding fragment thereof;   b. a monoclonal antibody or an antigen-binding fragment thereof;   c. a murine, chimeric, humanized or a human antibody or an antigen-binding fragment thereof;   d. an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3 or IgG4 antibody or antigen-binding fragment thereof; or   e. the binding molecule is an IgG4 isotype including the S228P mutation.   
     
     
         82 . An immunoconjugate comprising the alpha-synuclein binding molecule according to  claim 72 , optionally wherein the immunoconjugate crosses the blood brain barrier using a delivery vehicle or a blood brain barrier moiety, optionally wherein:
 a. the delivery vehicle comprises a liposome or extracellular vesicle;   b. the alpha-synuclein binding molecule is linked to a blood brain barrier moiety;   c. the blood brain barrier moiety is a polypeptide or a small molecule, preferably, a peptide, a receptor ligand, a single domain antibody (VHH), a scFv or a Fab fragment; or   d. wherein the blood brain barrier moiety binds a blood brain barrier receptor, preferably a transferrin receptor, insulin receptor or low-density lipoprotein receptor.   
     
     
         83 . A method for preventing, alleviating or treating diseases, disorders and abnormalities associated with alpha-synuclein, particularly with pathological alpha-synuclein or aggregated alpha-synuclein by administering the alpha synuclein binding molecule of  claim 72  to a subject, optionally wherein the aggregated alpha-synuclein is in the form of Lewy bodies, Lewy neurites or glial cytoplasmic inclusions, preferably wherein the disease, disorder or abnormality is:
 a. a synucleinopathy, or 
 b. Parkinson's disease (PD) (sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure and Lewy body dysphagia), Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (PDD)), Diffuse Lewy Body Disease (DLBD), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy), inclusion-body myositis, traumatic brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Frontotemporal dementia with Parkinsonism linked to chromosome 17 and Niemann-Pick type C1 disease), Down syndrome, Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (sporadic, familial and ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), prion diseases, Gerstmann-Straussler-Scheinker disease, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, Krabbe disease as well as other lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome), or rapid eye movement (REM) sleep behavior disorder, more preferably wherein the disease, disorder or abnormality is selected from the group consisting of Parkinson's Disease, Multiple System Atrophy, Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (PDD)) and Diffuse Lewy Body Disease. 
 
     
     
         84 . The method according to  claim 83  for preventing, slowing down, halting, retaining or improving the motor capabilities or motor deficits, cognitive capabilities or cognitive deficits, behavioral impairments or REM sleep disorders of a subject suffering from a synucleinopathy, wherein the synucleinopathy is multiple system atrophy (MSA) Parkinson's Disease, Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (PDD)) or Diffuse Lewy Body Disease. 
     
     
         85 . A method for diagnosing diseases, disorders and abnormalities associated with alpha-synuclein, particularly with pathological alpha-synuclein or aggregated alpha-synuclein, using the alpha-synuclein binding molecule according to  claim 72 . 
     
     
         86 . A method for:
 a. detecting alpha-synuclein in a sample obtained from a subject, the method comprising contacting the sample with the alpha-synuclein binding antibody or antigen-binding fragment thereof of  claim 72  and detecting binding of the antibody or antigen-binding fragment thereof in order to detect alpha-synuclein in the sample, or   b. quantifying alpha-synuclein in a sample obtained from a subject, the method comprising contacting the sample with the alpha-synuclein binding antibody or antigen-binding fragment thereof of  claim 72  and quantifying alpha-synuclein in a sample based on the level of binding of the antibody or antigen-binding fragment thereof to alpha-synuclein.   
     
     
         87 . A method for diagnosing a disease, disorder or condition associated with alpha-synuclein comprising performing the quantifying method of  claim 86  wherein:
 a. higher levels of alpha-synuclein in the sample compared with a control level based on healthy subjects are indicative of a disease, disorder or condition associated with alpha-synuclein; or 
 b. similar or higher levels of alpha-synuclein in the sample compared with a diseased control level are indicative of a disease, disorder or condition associated with alpha-synuclein; or 
 a method for classifying a disease, disorder or condition associated with alpha-synuclein comprising: 
 a. performing the quantifying method of  claim 86 , wherein
 i. higher levels of alpha-synuclein in the sample compared with a control level based on healthy subjects are indicative of a disease, disorder or condition associated with alpha-synuclein; or 
 ii. similar or higher levels of alpha-synuclein in the sample compared with a diseased control at a certain stage of disease are indicative of that stage of disease, disorder or condition associated with alpha-synuclein; and 
 
 b. classifying the disease, disorder or condition associated with alpha-synuclein. 
 
     
     
         88 . A method for monitoring a disease, disorder or condition associated with alpha-synuclein at two or more time points using samples from a subject comprising contacting the samples with an alpha-synuclein binding antibody or antigen-binding fragment thereof of  claim 72 , wherein:
 a. higher levels of alpha-synuclein in the later sample compared with one or more earlier samples are indicative of progression of a disease, disorder and/or condition associated with alpha-synuclein;   b. lower levels of alpha-synuclein in the later sample compared with one or more earlier samples are indicative of regression of a disease, disorder and/or condition associated with alpha-synuclein; or   c. no significant change of levels of alpha-synuclein in the later sample compared with one or more earlier samples are indicative of lack of progression of a disease, disorder or condition associated with alpha-synuclein; or   
       a method for selecting a therapy for treatment of a disease, disorder or condition associated with alpha-synuclein comprising contacting samples taken before and after treatment with the therapy with an alpha-synuclein binding antibody or antigen-binding fragment thereof of  claim 72 , wherein:
 a. lower levels of alpha-synuclein in the sample taken after treatment compared with the sample taken before treatment are indicative of successful treatment of a disease, disorder or condition associated with alpha-synuclein and thus the therapy is selected for treatment; 
 b. no significant change of levels of alpha-synuclein in the sample taken after treatment compared with the sample taken before treatment are indicative of successful treatment of a disease, disorder or condition associated with alpha-synuclein and thus the therapy is selected for treatment; 
 c. a decline in the rate of increase of levels of alpha-synuclein between samples taken during treatment compared with samples taken before treatment are indicative of successful treatment of a disease, disorder or condition associated with alpha-synuclein and thus the therapy is selected for treatment; 
 d. higher levels of alpha-synuclein in the sample taken after treatment compared with the sample taken before treatment are indicative of unsuccessful treatment of a disease, disorder or condition associated with alpha-synuclein and thus the therapy is not selected for treatment; or 
 e. no decline in the rate of increase of levels of alpha-synuclein between samples taken during treatment compared with samples taken before treatment are indicative of unsuccessful treatment of a disease, disorder or condition associated with alpha-synuclein and thus the therapy is not selected for treatment. 
 
     
     
         89 . A method for assessing a candidate therapy for a disease, disorder or condition associated with alpha-synuclein, the method comprising, following treatment of one or more subjects, contacting samples from the one or more treated subjects with an antibody or antigen-binding fragment of  claim 72 , wherein lower levels of alpha-synuclein in the samples compared with levels in corresponding samples from subjects not treated with the therapy are indicative of successful treatment of a disease, disorder or condition associated with alpha-synuclein, optionally wherein the method is performed at multiple time points in matched samples between the treatment and placebo groups in order to monitor the effectiveness of the candidate therapy over a defined time period or comprises contacting samples from the one or more treated subjects and the subjects not treated with the therapy with an antibody or antigen-binding fragment of  claim 72  prior to treatment, with the therapy or placebo respectively, to determine base levels of alpha-synuclein. 
     
     
         90 . The method according to  claim 86  wherein the alpha-synuclein comprises, consists essentially of or consists of pathological alpha-synuclein or aggregated alpha-synuclein and wherein the disease, disorder or condition associated with alpha-synuclein is Parkinson's disease (PD) (sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure and Lewy body dysphagia), Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (PDD)), Diffuse Lewy Body Disease (DLBD), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy), inclusion-body myositis, traumatic brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Frontotemporal dementia with Parkinsonism linked to chromosome 17 and Niemann-Pick type C1 disease), Down syndrome, Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (sporadic, familial and ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), prion diseases, Gerstmann-Straussler-Scheinker disease, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, Krabbe disease as well as other lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome), or rapid eye movement (REM) sleep behavior disorder. 
     
     
         91 . The alpha-synuclein antibody or antigen-binding fragment thereof of  claim 72  for research use, in particular as an analytical tool or reference molecule. 
     
     
         92 . A pharmaceutical composition comprising the alpha-synuclein binding molecule of  claim 72  and a pharmaceutically acceptable carrier or excipient. 
     
     
         93 . A nucleic acid, recombinant expression vector comprising a nucleic acid, host cell comprising a nucleic acid or cell-free expression system comprising a recombinant expression vector which comprises a nucleic acid, wherein the nucleic acid encodes the alpha-synuclein binding molecule of  claim 72 , optionally wherein the nucleic acid comprises a nucleotide sequence as provided in SEQ ID NO: 618, SEQ ID NO: 619, SEQ ID NO: 628, SEQ ID NO: 629, SEQ ID NO: 638, SEQ ID NO: 639, SEQ ID NO: 648, SEQ ID NO: 649, SEQ ID NO: 658, SEQ ID NO: 659, SEQ ID NO: 668, SEQ ID NO: 669, SEQ ID NO: 678, SEQ ID NO: 679, SEQ ID NO: 688, SEQ ID NO: 689, SEQ ID NO: 698, SEQ ID NO: 699, SEQ ID NO: 708, SEQ ID NO: 709, SEQ ID NO: 718, SEQ ID NO: 719, SEQ ID NO: 728, SEQ ID NO: 729, SEQ ID NO: 738, SEQ ID NO: 739, SEQ ID NO: 748, SEQ ID NO: 749, SEQ ID NO: 758, SEQ ID NO: 759, SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 789, SEQ ID NO: 798, SEQ ID NO: 799, SEQ ID NO: 808, SEQ ID NO: 809, SEQ ID NO: 818, SEQ ID NO: 819, SEQ ID NO: 828, SEQ ID NO: 829, SEQ ID NO: 838, SEQ ID NO: 839, SEQ ID NO: 848 or SEQ ID NO: 849, optionally wherein the nucleic acid is a part of a viral vector for targeted delivery to the blood brain barrier or any other cell type in the CNS, optionally wherein the viral vector is a recombinant adeno-associated viral vector (rAAV), preferably a recombinant adeno-associated viral vector selected from AAV1 to AAV12. 
     
     
         94 . A method for producing an isolated alpha-synuclein binding molecule, in particular an antibody or antigen-binding fragment thereof, comprising the steps of:
 a. culturing the host cell or the cell-free expression system of claim  93  under conditions suitable for producing the alpha-synuclein binding molecule, in particular the antibody or antigen-binding fragment thereof, and   b. isolating the alpha-synuclein binding molecule, in particular the antibody or antigen-binding fragment thereof.   
     
     
         95 . A kit for diagnosis of a disease, disorder or abnormality associated with alpha-synuclein, comprising an alpha-synuclein binding molecule according to  claim 72 , optionally further comprising a container.